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Published on: January 18, 2017
Therapeutic blockade of Foxp3 in experimental breast cancer models
Mariela A Moreno Ayala1, María Florencia Gottardo1,2, Mercedes Imsen1
1Instituto de Investigaciones Biomédicas (INBIOMED), Facultad de Medicina, CONICET, Universidad de Buenos Aires, Paraguay 2155, piso 10, Buenos Aires, C1121ABG, Argentina.
Purpose:
Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function.
Methods:
Mice bearing established syngeneic LM3 and 4T1 breast tumors were treated with antitumor DC vaccines and a synthetic peptide (P60) that has been shown to inhibit Foxp3.
Results:
Treatment with P60 improved the therapeutic efficacy of DC vaccines in these experimental models. In addition, monotherapy with P60 inhibited tumor growth in immunocompetent as well as in immuno-compromised animals bearing established tumors. We found expression of Foxp3 in human and murine breast tumor cells. P60 inhibited IL-10 secretion in breast cancer cells that expressed Foxp3.
Conclusions:
Our results suggest that Foxp3 blockade improves the therapeutic efficacy of DC vaccines by inhibition of Tregs and through a direct antitumor effect. This strategy could prove useful to neutralize the immunosuppressive microenvironment and to boost antitumor immunity in breast cancer.
Insights
A novel peptide (P60) enhances dendritic cell (DC) vaccines by blocking Foxp3, improving cancer immunotherapy. This approach targets regulatory T cells (Tregs) and directly inhibits tumor growth in breast cancer models.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Regulatory T cells (Tregs) expressing Foxp3 suppress the immune response, limiting the effectiveness of cancer immunotherapies.
- Optimizing dendritic cell (DC) vaccines requires strategies to overcome the immunosuppressive tumor microenvironment.
Purpose of the Study:
- To investigate the potential of inhibiting Foxp3 to enhance the antitumor efficacy of DC vaccines.
- To evaluate a synthetic peptide (P60) as a Foxp3 inhibitor for cancer immunotherapy.
Main Methods:
- Mice with established breast tumors (LM3 and 4T1) were treated with DC vaccines and the Foxp3-inhibiting peptide P60.
- Foxp3 expression in human and murine breast cancer cells was assessed.
- Interleukin-10 (IL-10) secretion was measured in Foxp3-expressing breast cancer cells.
Main Results:
- P60 treatment significantly improved the therapeutic efficacy of DC vaccines in preclinical breast cancer models.
- P60 monotherapy demonstrated antitumor effects in both immunocompetent and immunocompromised mice.
- Foxp3 was detected in both murine and human breast tumor cells, and P60 inhibited IL-10 secretion in these cells.
Conclusions:
- Foxp3 blockade via P60 enhances DC vaccine efficacy by inhibiting Tregs and exerting direct antitumor effects.
- This strategy offers a promising approach to neutralize the immunosuppressive tumor microenvironment and boost antitumor immunity in breast cancer.
